Asthma is disease manifested by chronic inflammation exacerbated by environmental insults such as allergens, infectious agents and irritants. The innate and adaptive host responses recognize and eradicate the effect of these insults to restore tissue integrity and homeostasis. In our proposal, we focus on the critical innate immune factors surfactant protein A (SP-A), a lipid constituent of surfactant, palmitoyl-oleoyl- phosphatidylglycerol (POPG) and Toll-like receptor interacting protein (Tollip). We show that these mediators each perform critical negative regulatory functions that synergize to offer protection from type 2 inflammation and viral exacerbations. SP-A modulates inflammation associated with type 2 inflammation and viral infections but exhibits genetic heterogeneity altering its function. Tollip, a 30 kDa adaptor protein that is also genetically heterogeneous, is recognized as a negative regulator of toll-like receptor (TLR) signaling. A phospholipid contained in surfactant, POPG is known to play a critical role in regulating innate immunity by inhibiting activation of multiple TLRs. Our central hypothesis to be tested is that dysfunction of SP-A, Tollip and POPG occurs as a consequence of genetic polymorphisms and degradative events which significantly alter their function in the setting of asthma and viral infection, leading to exacerbations and persistence of inflammation. With an underpinning of innate immune dysfunction, the projects utilize distinct but overlapping clinically relevant models of exacerbations in asthma (rhinovirus (RV), respiratory syncytial virus (RSV)), type 2 inflammation (IL-13 exposure, HDM animal models) from distinct molecular perspectives (SP-A, Tollip, POPG), effectively creating a network rather than linear approach to understanding the mechanism(s) of innate immune dysfunction in type 2 inflammation and asthma exacerbations. This program proposes three interrelated projects: Project 1 will determine how SP-A suppresses allergic inflammation through disruption of IL-13-dependent signaling pathways, but due to genetic heterogeneity, its function is impaired in asthma. Specific SP-A peptides can rescue this dysfunction, offering a novel therapeutic approach for asthma. Project 2 will determine the relationship between genetically determined variations in Tollip expression and airway responses to viral infections in the setting of type 2 inflammation. Project 3 will critically test the activity of POPG and SP-A as novel endogenous molecular mechanisms for disrupting infections due to RV and RSV, two viruses known to exacerbate asthma. We also include two cores: an Administrative Core and a Clinical Core, both which serve all projects equally and are responsible for the scientific, advisory, fiscal, human subject and data management/statistical aspects of the program. In this U19 program, we propose novel mechanisms of innate immune dysfunction and potential treatments that not only modulate the resolution of allergic inflammation, but regulate host-pathogen interactions in the setting of allergic inflammation.